There is no known treatment for cerebral amyloid angiopathy (CAA), an important cause of hemorrhagic stroke and increasingly recognized contributor to vascular cognitive impairment and neurological dysfunction. We propose to use our prospective longitudinal study of patients with CAA-related intracerebral hemorrhage as the centerpiece of both a multidisciplinary investigation of the mechanisms by which CAA affects neurological function and a clinical research training program for early investigators in the fields of stroke and vascular cognitive impairment. Building on the Principle's Investigator's groundbreaking success in defining the diagnosis, clinical course, and pathophysiology of CAA, the proposed studies focus on 1) the interrelationship between CAA-related hemorrhages and white matter lesions, 2) the effects of these lesions on cognition, depressive symptoms, functional skills, and gait, and 3) their association with genetic and biochemical risk factors. Successful completion of these studies will represent a key step towards developing diagnostic markers, outcome markers, and candidate treatments for future trials aimed at prevention of CAA-related hemorrhage and cognitive dysfunction. The studies will be performed as part of long-standing collaborations with investigators (drawn from the rich Harvard Medical School research environment) at the Martinos Center for Biomedical Imaging (Dr. A. Gregory Sorensen, Co-Director), Program in Medical and Population Genetics (Dr. David Altschuler, Director), and Biostatistics Center (Dr. Rebecca Betensky). The multidisciplinary team of collaborators will also serve as the basis for an intensive patient-oriented research training program in key aspects of neurological research, including principles of patient-oriented research, neurological and cognitive assessment of intracerebral hemorrhage subjects, computer-assisted radiographic image analysis, human genetic analysis, and biostatistics. The Principle Investigator has an outstanding record of mentoring early clinical investigators, demonstrated by trainees' success in publication, research funding, and transition to independent careers. The Principle Investigator's consistent success in defining biologically based approaches to compelling research questions and obtaining NIH-funded R01 support make it extremely likely that the proposed studies will succeed both as cutting-edge clinical investigation and tools for training a new generation of stroke investigators. [unreadable] [unreadable] [unreadable]